During the past decades, asymmetric organocatalysis and organometallic catalysis made a breakthrough and became methodologies of choice for the synthesis of chiral substances on laboratory as well as on industrial scale. Numerous chiral catalysts are formed by complexation of a phosphorus ligand with a transition metal. Sometimes, organophosphorus compounds may also be directly used as organocatalysts. In this latter case, organophosphorus derivatives may be used as counter ions, as organocatalysts in asymmetric reactions under phase transfer conditions or as Lewis bases.
As no “universal” ligand exists for asymmetric catalysis, the synthesis and the study of new chiral ligands remains a field in permanent development.
In most cases, the organophosphorus compounds used in asymmetric reactions derive from naturally occurring substances or easily accessible precursors (for example binaphthol, tartaric acid, amino-acids, carbohydrates . . . ) in which the chirality is on the carbon skeleton. In organophosphorus organometallic catalysts, chirality of the carbon skeleton is transferred to the coordination sphere of the metal through the phosphorus substituents. The most popular chiral organophosphorus compounds used in asymmetric reactions, such as Quinap, Binap, XyliPhos or DuPhos, have axial- or planar-chirality or still chirality due to a cycle.
Organophosphorus compounds bearing the chirality on the phosphorus centers (P-chirogenic), such as Dipamp or MiniPhos, are very interesting from an industrial and stereochemical point of view in organometallic catalysis. In fact, they allow introducing directly a sterically and electronically well-defined architecture around the metal center, depending on the nature of the substituents present on the phosphorus atom. The resulting chiral environment is more efficient than the one obtained by the transfer of chirality from the carbon skeleton.
P-chirogenic organophosphorus compounds are also interesting as organocatalysts. They may be used as phosphonium salts, acido-basic derivatives or conduce to obtain low valence chiral complexes.
However, P-chirogenic organophosphorus compounds are not often used in asymmetric catalysis due to difficulties of synthesis and to delicate procedures of resolution of optically active compounds.
The asymmetric synthesis of organophosphorus ligands has made significant progresses in the last decade due to the introduction of borane as protecting group of the phosphorus atom. Organophosphorus borane complexes are stable, often crystalline compounds, which give clean reactions either on the P-center or on the alpha or beta position of the phosphorus substituents. The borane decomplexation can easily be achieved to give quantitatively the corresponding P(III)-compound with complete retention of configuration on the phosphorus center (Uziel J., Darcel C., Moulin D., Bauduin C. and Jugé S., Tetrahedron: Asymmetry, 2001, 12, 1441-1449).
Today, the enantioselective synthesis of P-chirogenic organophosphorus compounds is essentially achieved by two approaches using phosphine boranes acting either as electrophilic or as a nucleophilic reagents.
In the electrophilic approach, phosphinite borane 1 or chlorophosphine borane (VII) may be prepared using a methodology starting from ephedrine (Jugé S., Stephan M., Laffitte J. A. and Genêt J. P., Tetrahedron Lett., 1990, 31, 6357-6360; Bauduin C., Moulin D., Kaloun E. B., Darcel C. and Jugé S., J. Org. Chem., 2003, 68, 4293-4301). These electrophilic reagents may then be used to prepare ferrocenyl- and silyl-bridged diphosphines.

In the nucleophilic approach, carbanions in alpha-position of phosphine boranes 3 can be obtained either by deprotonation of a methylphosphine borane or via a dynamic kinetic resolution of a dimethylphosphine borane in presence of sparteine (Muci A. R., Campos K. R. and Evans D. A., J. Am. Chem. Soc., 1995, 117, 9075-9076; Yamada Y. and Imamoto T., J. Org. Chem., 1999, 64, 2988-2989). The reaction of these carbanions with various electrophiles leads to ethano- or methano-bridged diphosphines.
Another nucleophilic approach uses a dynamic kinetic resolution of racemic secondary phosphine boranes in presence of sparteine. The phosphide lithium borane 4 (M=Li) obtained under these conditions may be used for the synthesis of pincer ligands via the formation of two P—C bonds. The metallophosphide boranes 4 are highly important building-blocks for the synthesis of novel classes of P-chirogenic ligands. However, the preparation of these compounds with high stereoselectivities was restricted until recently to lithiated examples with sterically hindered substituents like t-butyl or adamantly groups (Crépy K. V. L., Imamoto T., Top. Curr. Chem., 2003, 229, 1-40; Imamoto T., J. Synth. Org. Chem., Jpn., 2007, 65, 1060-1069).
Therefore, there remains a need for the development of new methods of synthesis of optically active phosphine ligands. Such methods should be versatile enough to easily lead to broad libraries of optically active phosphine ligands that may be tested for asymmetric synthesis applications.
Recently, the Applicant has developed a new methodology for the preparation of P-chirogenic secondary phosphine boranes (V) starting from chlorophosphine boranes (VII). This unprecedented methodology is based on halogen/metal exchange reactions at low temperature which proceed with complete retention of configuration on the P-atom (scheme 1). The subsequent protonation of the intermediate phosphide boranes 4 affords secondary phosphine boranes of general formula (V) with excellent enantiomeric excess (ee>90%).

As a result of intensive research conducted for the development of new optically active phosphine compounds, the Applicant found that new classes of ligands or organocatalysts of general formula (I) may be obtained with very high enantiomeric excess starting from chlorophosphine boranes (VII) (scheme 2). The synthetic approach leading to compounds (I) was found to be very versatile, giving access to a wide variety of products and easy modification of their substituents.

The process developed by the Applicant for producing compounds (I) involves the synthesis of intermediate phosphine boranes of general formula (IV) bearing an activated group in the ortho position (scheme 2).
The process of the invention especially enables the synthesis of enantioenriched ortho-functionalized phosphines, such as for example o-boronate, o-silano phosphines and o-hydroxymethyl.
O-boronates phosphines are ambiphiles, i.e. bearing both Lewis acid and base, and are of particular interest in the fields of synthesis and catalysis for their use as ligand. To the Applicants-s knowledge, no chiral borane or boranate phosphine has been described so far.
Chiral enantiopure o-hydroxymethyl phosphines are also particularly interesting as they can be used both as asymmetric organocatalyst and as ligand in organometallic catalysis. For example, Nakamura reported the use of non-P-chirogenic phosphines bearing a hydroxymethylated chelating chain for Ni-catalyzed coupling reactions (Yoshikai N., Matsuda H. and Nakamura E., J. Am. Chem. Soc. 2009, 131, 9590-9599).
The only example of preparation of P-chirogenic phosphines bearing a hydroxymethylated chelating chain has been reported by Beak et al. (Tollefson M., Li J. and Beak P., J. Am. Chem. Soc., 1996, 118, 9052-9061). It involves phosphinite rearrangement and the methods of synthesis is not versatile.
o-hydroxymethyl phosphines may also be used as precursors of o-hydroxymethyl phosphonium salts, which are known to be synthetically useful in Wittig reactions (Marcoux D. and Charette A., Adv. Synth. Catal. 2008, 350, 2967-2974; McNulty J. and Keskar K., Tetrahedron Letters, 2008, 49, 7054-7057). It may also be envisaged to use o-hydroxymethyl phosphonium salts as new interesting organocatalysts.
Applications in asymmetric catalysis of P-chirogenic organophosphorus compounds (I) as ligands have been explored. Especially, compounds (I) may be used as ligands of transition metal, such as rhodium or palladium, and the resulting complexes may be suitable for asymmetric catalyzed hydrogenation, allylation, hydroformylation or carbonylation reactions. Phosphonium salts of compounds (I) may also be used in asymmetric reactions using phase transfer conditions such as fluoration or cyanation.